Defining a new vision for the retinoblastoma gene: report from the 3rd International Rb Meeting.

Rubin and Sage Cell Division 2013, 8:13
http://www.celldiv.eom/content/8/1 /1 3

DO CELL DIVISION

COMMENTARY Open Access

Defining a new vision for the retinoblastoma
gene: report from the 3rd International Rb
Meeting

Seth M Rubin 1 * 1 and Julien Sage 2 * +
Abstract

The retinoblastoma tumor suppressor (Rb) pathway is mutated in most, if not all human tumors. In the G0/G1
phase, Rb and its family members p1 07 and pi 30 inhibit the E2F family of transcription factors. In response to
mitogenic signals, Cyclin-dependent kinases (CDKs) phosphorylate Rb family members, which results in the disruption
of complexes between Rb and E2F family members and in the transcription of genes essential for S phase progression.
Beyond this role in early cell cycle decisions, Rb family members regulate DNA replication and mitosis, chromatin
structure, metabolism, cellular differentiation, and cell death. While the RB pathway has been extensively studied in the
past three decades, new investigations continue to provide novel insights into basic mechanisms of cancer development
and, beyond cancer, help better understand fundamental cellular processes, from plants to mammals. This meeting
report summarizes research presented at the recently held 3rd International Rb Meeting.

Keywords: Retinoblastoma, Rb, pi 07, pi 30, E2F, CDK, Cyclin

Background

The Rb tumor suppressor was cloned more than 25 years
ago from children with retinoblastoma [1-4]. This seminal
discovery led to an intense research effort culminating in
the elucidation of the Rb pathway and fundamental mech-
anisms governing the Gl/S transition of the cell cycle. It is
now understood that regulators and mediators of Rb func-
tion are deregulated in a large set of diverse pediatric and
adult tumors. In the last 10 years, a number of experi-
ments have shown that Rb controls many biological pro-
cesses beyond cell cycle entry, including at other stages of
the cell cycle, for cell survival and during cellular differen-
tiation. At the molecular level, while E2F transcription
factors are known to be critical mediators of Rb function,
the Rb protein binds to more than 150 other proteins,
such as tissue-specific transcription factors and chromatin
remodeling enzymes (see [5-9] for recent reviews).

Major challenges in the field include determining
the biochemical mechanisms carried out by multiple

* Correspondence: srubin@ucsc.edu; julsage@stanford.edu
+ Equal contributors

'Department of Chemistry and Biochemistry, University of California, Santa
Cruz, CA 95064, USA

Full list of author information is available at the end of the article

Bio Med Central

Rb-containing complexes in cells, exploring the role of
novel Rb functions in tumor suppression, and identifying
the combinations of genetic alterations that result in
tissue-specific cancers. The ultimate goal of the field is
to discover novel therapeutic approaches to stop or slow
the growth of human tumor cells with mutations in the
Rb pathway. Accordingly, research on Rb and the net-
works around Rb in cells remains intense with publica-
tion of nearly 1,000 relevant journal articles a year.

Two previous international Rb conferences were orga-
nized in 2009 and 2011 in Toronto, Canada by Eldad
Zacksenhaus and Rod Bremner. The success of these
first two meetings coalesced a large group of investiga-
tors with a strong interest in participating in a scientific
meeting focusing on the Rb pathway, which would be
organized every other year in a rotating manner by active
participants. 88 researchers in the Rb field recently gath-
ered to exchange results and ideas at the 3rd International
Rb Meeting, which was held October 7-10, 2013, in
Monterey, CA, USA. The conference included 33 oral pre-
sentations and 45 posters. While we cannot summarize
here all these studies, many of them unpublished, we high-
light several topics discussed.

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Rubin and Sage Cell Division 2013, 8:13
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Meeting summary

A number of presentations focused on the disease of
retinoblastoma, the pediatric tumor after which the Rb
gene was named. The recent publication of the first hu-
man retinoblastoma cancer genomes by Michael Dyer's
group emphasized the very low number of alterations
found in these tumors and suggested an epigenetic mech-
anism of tumorigenesis upon loss of Rb function [10-12].
Claudia Benavente from the Dyer lab presented new ana-
lyses of the genomes of pediatric tumors, including can-
cers with RB mutations, and the St Jude's Children's
Research Hospital now provides access to a large number
of data and reagents (https://hospital.stjude.org/dbstp/). A
number of other groups, including those of Josephine
Dorsman and David MacPherson, are performing genom-
ics studies on patient-derived retinoblastomas as well as
tumors from genetically engineered mice [13-18]. While
some of the human tumors clearly develop with few DNA
alterations beyond Rb loss, these alterations may still pro-
vide key insights into the mechanisms of tumorigenesis
upon loss of Rb function. Genomics and epigenomics
studies of retinoblastoma and other Rb-deficient tumors
are still in their infancy and, combined with cellular sys-
tems and mouse models, may identify novel therapeutic
targets. In stimulating new work that could complement
mouse models, David Cobrinik and his colleagues are
exploring the mechanisms of cancer initiation in human
fetal retinal cells upon Rb loss [19].

While Rb was identified nearly three decades ago,
there are still no targeted therapies to treat Rb-deficient
tumors. In an exciting development, several presenters
discussed remarkable progress towards developing such
therapeutics. Work from the laboratory of Erik Knudsen
has underscored the differential response of Rb wild-
type and Rb-deficient breast cancer cells to chemother-
apy, the latter often being more sensitive to classical
chemotherapeutic agents [20,21]. Recent results from
the laboratory of Rod Bremner demonstrate that redu-
cing E2F or Cdk2 activity using small molecule inhibi-
tors, even for a short period of time early during tumor
development in mice, may be sufficient to prevent the
growth of retinoblastoma [22]. These experiments and
ongoing work suggest that such "prevention" strategies
may help significantly reduce tumor burden in familial
cases or when tumors are detected early. Beyond this
targeted approach, other groups, including those of
Eldad Zacksenhaus and Maria Alvarado-Kristensson, are
performing high throughput screens to identify small
molecules that may specifically block the expansion of
Rb mutant cells, including Rb-deficient triple negative
breast cancer [23].

One of the most interesting aspects of the conference
was the large number of presentations introducing novel
functions for Rb pathway members. The groups of Peter

Sicinski, Philip Hinds, and Philipp Kaldis all identified
novel functions for Cyclins and CDKs using state-of-
the-art mouse genetics approaches. These functions go
beyond the classical cell cycle progression roles for these
kinase complexes, and extend to the control of differenti-
ation and organ/tissue function [24]. Similarly, the groups
of Nicholas Dyson, Maxim Frolov, William Henry, David
Johnson, Jacqueline Lees, and Chiaki Takahashi found
new roles for Rb and E2F in various central cellular pro-
cesses, including mitochondrial function, metabolism, the
transcription of small RNAs, RNA translation, DNA
repair, or cell migration [7,25,26]. Work from the labora-
tories of Timothy Hallstrom, Gustavo Leone, James Pipas
(with Maria Teresa Saenz Robles), Julien Sage, and Ruth
Slack underscored functional interactions between E2F
transcription factors and other transcription factors such
as beta-catenin, Sox2, Myc, YAP, or FoxO, uncovering
complex regulatory networks controlling multiple cellular
processes (e.g. [27-31]). The number of partners for Rb
and E2F family members and the multitude of functions
that they exert in cells bring the field to a new level of
complexity.

A number of groups, including the laboratories of
Ashby Morrison, Elizaveta Benevolenskaya, Jesus Paramio,
and Fred Dick presented new evidence of a role for Rb
in regulating chromatin structure using a combination
of biochemical, molecular, and genetic studies [32,33].
Several groups (Seth Rubin, Joe Lipsick, James DeCaprio,
Valerie Reinke, Susan Strome) have begun to explore the
mechanisms of action of the DREAM (DP, Rb, E2F, and
MuvB) and Myb-MuvB complexes in cells, including the
identity and the structure of these complexes, how they
control gene expression during the cell cycle and develop-
ment, and how the complexes are regulated [34-36].

Another new area of investigation described at the con-
ference was the analysis of cell cycle progression in single
cells by Jan Skotheim, Lingchong You, and Tobias Meyer
labs (postdoctoral fellow Sabrina Spencer) (e.g. [37-39]).
When presented next to new results from the laboratory
of Steven Dowdy (by Manuel Kaulich) on the kinetics of
Rb phosphorylation by CDKs, these experiments help re-
define the restriction point and when cells are committed
to enter and conclude a cell cycle. Together these studies
may soon modify the old textbook view of the Gl/S
checkpoint and the role of CDK activity in defining this
checkpoint.

The Rb field has been primarily driven by the role of the
Rb pathway in cell cycle control and cancer. However,
interesting work in yeast (Jan Skotheim), in C. elegans
(Susan Strome, Valerie Reinke), in D, melanogaster
(Maxim Frolov, Nicholas Dyson, Joe Lipsick), and in plants
(Wilhelm Gruissem and Arp Schnittger) was presented
on the role of Rb-like and E2F-like molecules [35,40-47].
These studies further highlight a role of Rb in cell fate

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Page 3 of 4

decisions that may have been conserved during evolution
from fungi to mammals and plants [48] .

Conclusions

The Rb field is vibrant and relevant to many areas of
biology, including cancer biology, developmental biology,
stem cell biology, and regenerative medicine. A major
goal of the Rb meeting, and its highest impact, is to offer
a unique forum for building a community of scientists
working together, advancing scientific knowledge. The
3rd International Rb Meeting offered hope that 20 years
of molecular studies would soon translate into novel
therapeutic options in a large number of patients. At the
same time, the conference further highlighted the need
for many more years of biochemical, structural, cellular,
and organismal studies to better understand the regula-
tion and the mode of action of Rb in plants and animals.
The 4th International Rb Meeting, which will take place
in Boston in 2015 and will be organized by Drs. J. Lees
(MIT), N. Dyson (MGH, Harvard Medical School), and
J. DeCaprio (DFCI, Harvard Medical School), will with
no doubt reveal further unexpected findings and con-
tinue to strengthen this field of intense research.

Abbreviations

Rb: retinoblastoma; CDK: Cyclin-dependent kinase.
Competing interests

The authors declare that they have no competing interests.
Authors' contributions

Both authors contributed equally to this manuscript and are listed in
alphabetical order. Both authors read and approved the final manuscript.

Acknowledgements

We would like to thank all the participants of the conference for
contributing to its success and for sharing new and unpublished data,
especially the steering committee, as well as all the speakers for helping us
write this meeting summary. We are most grateful to the generous sponsors
of the meeting: the Alex's Lemonade Stand Foundation (ALSF), the California
Institute for Regenerative Medicine (CIRM), the California Tobacco-Related
Disease Research Program (TRDRP), the Stanford Cancer Institute, and the
Lucille Packard Children's Hospital at Stanford. Research on Rb in the Sage
lab is supported by the Leukemia and Lymphoma Society, the ALSF, the NIH
(R01 CA1 14102 and R21 CA167104). JS is the Harriet and Mary Zelencik Scientist
in Children's Cancer and Blood Diseases. Research on Rb in the Rubin lab is
supported by the NIH (R01 CA1 32685).

Author details

'Department of Chemistry and Biochemistry, University of California, Santa
Cruz, CA 95054, USA, departments of Pediatrics and Genetics, Stanford
University, Stanford, CA 94305, USA.

Received: 19 November 2013 Accepted: 20 November 2013
Published: 21 November 2013

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Cite this article as: Rubin and Sage: Defining a new vision for the
retinoblastoma gene: report from the 3rd International Rb Meeting. Cell
Division 2013 8:13.

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